The cGAS-STING pathway in tumor immunity: dual roles, regulatory mechanisms, and precision therapeutic strategies.

Authors

Haiyan Jiang, Zhanzhan Li, Xia Li, Lulu Yu, Jiacheng Sun, Yuntian Shen, Hualin Sun, Lei Qi

Published in

Frontiers in pharmacology. Volume 17. Pages 1844637. Epub Jul 08, 2026.

Abstract

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, the core DNA-sensing mechanism in innate immunity, plays a pivotal role in linking tumorigenesis and the immune response. This review systematically elucidates the molecular activation mechanisms of this pathway and its complex regulatory networks within tumors, with a particular focus on analyzing its dual functions-tumor immune surveillance versus tumor promotion-and the determining factors involved. Current research indicates that acute activation of the cGAS-STING pathway potently suppresses tumors by inducing type I interferon responses, thereby promoting dendritic cell (DC) maturation and cytotoxic T lymphocyte infiltration. However, its chronic, persistent activation can paradoxically accelerate tumor progression and immune evasion by remodeling the immunosuppressive tumor microenvironment (TME), inducing chronic inflammation, and enhancing the intrinsic malignant phenotypes of tumor cells. Tumor cells tightly regulate the activity of this pathway through multiple mechanisms, including epigenetic silencing, aberrant post-translational modifications, autophagy-dependent degradation, and tumor microenvironment remodeling. Based on these findings, this review comprehensively summarizes therapeutic strategies targeting the cGAS-STING pathway. These include the latest advancements in STING agonist development, optimization strategies for combination therapies, and innovative applications of nano-delivery systems. Furthermore, we delve into the critical challenges hindering current clinical translation, including pharmacokinetic limitations, mechanisms of tumor resistance, STING genetic polymorphisms, and safety concerns. Finally, we explore future research directions, encompassing precision modulation strategies, personalized therapeutic approaches, and novel delivery systems, aiming to provide a theoretical foundation and innovative insights for the next generation of cancer immunotherapies centered on the cGAS-STING pathway.

PMID:
42488575
Bibliographic data and abstract were imported from PubMed on 23 Jul 2026.

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